The present invention relates to platinum (II) compounds effective for treating tumor cells and particularly effective to induce apoptosis in leukemia cells, breast cancer cells, prostate cancer cells, and brain cancer cells.
Cancer is a major disease that continues as one of the leading causes of death at any age. In the United States alone, it is anticipated that more than a half a million Americans will die of cancer in 2000. Currently, radiotherapy and chemotherapy are two important methods used in the treatment of cancer.
Considerable efforts are underway to develop new chemotherapeutic agents for more potent and specific anti-cancer therapy, presenting effective and efficient cytotoxicity against tumor cells, with minimal interference with normal cell function. Accordingly, there is an urgent need for the development and analysis of novel, effective anti-cancer agents.
The use of platinum (II) compounds as anti-cancer agents has been reported. For example, Cleare et al, Bioorganic Chem., 2, 187-210 (1973) discloses Pt2I2(EA)2 and Pt2Cl2(EA)2; Friedman et al discloses cis-Pt(NH2ETOH)2Cl2; Zimmerman et al, Inorganica Chimica Acta, 292 (1999) 127-130 discloses Pt2I2(EA)2 and Pt2Cl2(EA)2; U.S. Pat. No. 4,661,516 discloses cyclopropanedicarboxylato(trans-R,R-DACH) Pt(II)H2O; U.S. Pat. No. 4,758,588 discloses cyclopropanedicarboxylato(trans-R,R-DACH) Pt(II)H2O; U.S. Pat. No. 5,011,959 discloses 1,1,-cyclopropanedicarboxylato(trans-R,R-DACH) Pt(II)H2O; and U.S. Pat. No. 5,132,323 discloses 1,1,-cyclopropanedicarboxylato(trans-R,R-DACH) Pt(II)H2O. The present invention describes new platinum (II) compounds which are particularly effective for treating cancer cells.
In accordance with the purpose(s) of this invention, as embodied and broadly described herein, this invention, in one aspect, relates to platinum (II) compounds including one or more analogues of formula (I): 
wherein:
R1 and R2 are independently halo,
R3, R4, R5 and R6 are independently selected from the group consisting of: hydrogen, hydroxy, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C2-C6) alkenyl, (C3-C6) cycloalkenyl, aryl which may be unsubstituted or substituted with a halo, hydroxy, or (C1-C6) alkyl, (C1-C6) alkoxy, and (C1-C6) hydroxyalkyl, and
a) when R1=R2 
R7 and R8 are independently selected from the group consisting of: hydroxy, (C3-C6) alkyl, (C3-C6) cycloalkyl, (C2-C6) alkenyl, (C3-C6) cycloalkenyl, aryl which may be unsubstituted or substituted with a halo, hydroxy, or (C1-C6) alkyl, (C1-C6) alkoxy, and (C3-C6) hydroxyalkyl, or when taken together form a group of the formula: 
wherein m is 1 to 5 and R10 and R11 are independently selected from the group consisting of: hydrogen, halo, hydroxy, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkoxy, and (C1-C6) hydroxyalkyl; or
b) when R1xe2x89xa0R2,
R7 and R8 are independently selected from the group consisting of: hydroxy, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C2-C6) alkenyl, (C3-C6) cycloalkenyl, aryl which may be unsubstituted or substituted with a halo, hydroxy, or (C1-C6) alkyl, (C1-C6) alkoxy, and (C1-C6) hydroxyalkyl, or when taken together form a group of the formula: 
wherein m is 1 to 6 and R10 and R11 are independently selected from the group consisting of: hydrogen, halo, hydroxy, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkoxy, and (C1-C6) hydroxyalkyl;
or a pharmaceutically acceptable salt or ester thereof.
In a second aspect, the invention relates to platinum (II) compounds of formula (I) above, wherein:
R1 and R2 when taken together form a group of the formula: 
wherein: n is 1 to 6, and
a) when n=1 to 2,
R12 and R13 are independently selected from the group consisting of: hydrogen, halo, hydroxy, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkoxy, and (C1-C6) hydroxyalkyl, and
R7 and R8 are independently selected from the group consisting of: hydroxy, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C2-C6) alkenyl, (C3-C6) cycloalkenyl, aryl which may be unsubstituted or substituted with a halo, hydroxy, or (C1-C6) alkyl, (C1-C6) alkoxy, and (C1-C6) hydroxyalkyl, or when taken together form a group of the formula: 
wherein m is 1 to 5 and R10 and R11 are independently selected from the group consisting of: hydrogen, halo, hydroxy, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkoxy, and (C1-C6) hydroxyalkyl, or m is 6 and R10 and R11 are independently selected from the group consisting of: hydrogen, halo, hydroxy, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkoxy, and (C1-C6) hydroxyalkyl; or
b) when n=3 to 6,
R12 and R13 are independently selected from the group consisting of: hydrogen, halo, hydroxy, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkoxy, and (C1-C6) hydroxyalkyl, and
R7 and R8 are independently selected from the group consisting of: hydroxy, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C2-C6) alkenyl, (C3-C6) cycloalkenyl, aryl which may be unsubstituted or substituted with a halo, hydroxy, or (C1-C6) alkyl, (C1-C6) alkoxy, and (C1-C6) hydroxyalkyl, or when taken together form a group of the formula: 
wherein m is 1 to 6 and R10 and R11 are independently selected from the group consisting of: hydrogen, halo, hydroxy, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkoxy, and (C1-C6) hydroxyalkyl;
or a pharmaceutically acceptable salt or ester thereof.
Moreover, the present invention also relates to pharmaceutical compositions containing the aforementioned inventive compound(s) in combination with a pharmaceutically acceptable carrier.
The invention further provides a method of inducing apoptosis in a population of cells, including contacting the population of cells with the aforementioned inventive compound and/or composition(s) comprised of formula (I), wherein:
R1 and R2 are halo or when taken together form a group of the formula: 
wherein n is 1 to 6, and R12 and R13 are independently selected from the group consisting of: hydrogen, halo, hydroxy, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkoxy, and (C1-C6) hydroxyalkyl;
R3, R4, R5 and R6 are independently selected from the group consisting of: hydrogen, hydroxy, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C2-C6) alkenyl, (C3-C6) cycloalkenyl, aryl which may be unsubstituted or substituted with a halo, hydroxy, or (C1-C6) alkyl, (C1-C6) alkoxy and (C1-C6) hydroxyalkyl; and
R7 and R8 are independently selected from the group consisting of: hydrogen, hydroxy, (C1-C6) alkyl (C3-C6) cycloalkyl, (C2-C6) alkenyl, (C3-C6) cycloalkenyl, aryl which may be unsubstituted or substituted with a halo, hydroxy, or (C1-C6) alkyl, (C1-C6) alkoxy, and (C1-C6) hydroxyalkyl, or when taken together form a group of the formula: 
wherein m is 1 to 6, and R10 and R11 are independently selected from the group consisting of: hydrogen, halo, hydroxy, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkoxy, and (C1-C6) hydroxyalkyl;
or a pharmaceutically acceptable salt or ester thereof.
In yet another aspect, the invention provides a method of treating a subject with a tumor, wherein the method comprises administering to the subject a therapeutically effective amount of the aforementioned compound(s) or composition(s).
Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several experimental examples and together with the description, serve to explain the principles of the invention.